Synthesis and study of new aromatic oligoamide foldamers

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The folding of biomacromolecules plays such fundamental roles in life that its importance can never be overstated. For example, the folding of polypeptides results in the well-defined secondary structures and bewildering arrays of tertiary structures. These folded structures exhibit a wide variety of biological functions and activities. Folding oligomers having non-natural backbones, known as foldamers, are inspired by the folding of biomacromolecules, especially proteins. Over the last two decades, various unnatural foldamers have been developed to mimic the folding and functions of biomolecules and to explore potential applications. In this thesis, Chapter 1 provides a brief introduction on the development and characterization of foldamers. The topology of a foldamers can be controlled by a variety of factors, such as conformational preference of backbone modules, π-π stacking interactions, solvophobic interactions, metal-ligand coordination, i.e., designed oligomers fold based on non-covalent interactions, leading to the adoption of defined shape. In Chapter 2, aromatic oligoamide foldamers with reduced backbone constrains have been prepared. This class of oligoamides is derived from backbone-constrained oligoamides developed by our group that fold into well-defined conformations. Tuning the flexibility of the backbones of aromatic oligoamides is achieved by reducing the number of backbone-constraining H-bonds, leading to both improved synthetic efficiency and reversible folding-unfolding transitions. Folding with high cooperativity is observed with oligoamides having enhanced backbone flexibility. It was found that the stability of the folded conformations of the corresponding foldamers depends on chain length, temperature and solvents. Chapter 3 describes a continued study on a series of double-stranded oligoamide foldamers our group reported. These H-bonded, doubled-stranded foldamers, dubbed “duplex foldamers”, were previously found to adopt stable, folded conformations. Modifying the termini of these oligoamides has revealed the surprising impact of structural modification on the folding and dimer-chain equilibria of the resultant oligoamides. The equilibria between dimer and chains are strongly dependent on concentration and temperature. Chapter 4 is dedicated to a H-bonded duplex system that is responsive to external stimulus. Incorporation of a 2, 6-diamidopyridine unit into an oligoamide strand produces an acid-responsive H-bonded duplex. The presence of acid leads to a local conformational change in the corresponding protonated pyridine-containing strand, which interrupts the association of H-bonded duplex due to spatial mismatch. Removal of the stimulus allows complete restoration of the initial duplex.